1. Field of the Invention
The present invention generally relates to the transport and culturing of cells. Specifically, in one aspect, the present invention employs an anatomically specific device for regenerating at least first and second, juxtaposed tissues having different histologic patterns, which includes a first region having an internal three-dimensional architecture to approximate the histological pattern of the first tissue and a second region having an internal three-dimensional architecture to approximate the histologic pattern of the second tissue. In addition, the present invention relates to a domain for the trapping and controlled growth of cells as such functions relate to tissue regeneration. In particular, a permeable bioresorbable polymer assembly is designed in such a way as to allow tissue integration of the assembly while delaying, limiting or preventing total penetration through the device by tissue cells. Such an assembly can be used to: 1) provide space maintenance and regeneration of lost tissue external to the unit; and/or 2) control growth of tissue forming cells within the unit.
2. Statement of Related Art
The medical repair of bones and joints in the human body presents significant difficulties, in part due to the materials involved. Each bone has a hard, compact exterior surrounding a spongy, less dense interior. The long bones of the arms and legs, the thigh bone or femur, have an interior containing bone marrow. The material bones are composed of mainly is calcium, phosphorus, and the connective tissue substance known as collagen.
Bones meet at joints of several different types. Movement of joints is enhanced by the smooth hyaline cartilage that covers the bone ends and by the synovial membrane that lines and lubricates the joint. For example, consider a cross-section through a hip joint. The head of the femur is covered by hyaline cartilage. Adjacent to that cartilage is the articular cavity. Above the articular cavity is the hyaline cartilage of the acetabulum which is attached to the ilium. The ilium is the expansive superior portion of the hip bone.
Cartilage damage produced by disease such as arthritis or trauma is a major cause of physical deformity and dehabilitation. In medicine today, the primary therapy for loss of cartilage is replacement with a prosthetic material, such as silicon for cosmetic repairs, or metal alloys for joint realignment. The use of a prosthesis is commonly associated with the significant loss of underlying tissue and bone without recovery of the full function allowed by the original cartilage. The prosthesis is also a foreign body which may become an irritating presence in the tissues. Other long-term problems associated with the permanent foreign body can include infection, erosion and instability.
The lack of a truly compatible, functional prosthesis subjects individuals who have lost noses or ears due to burns or trauma to additional surgery involving carving a piece of cartilage out of a piece of lower rib to approximate the necessary contours and insert the cartilage piece into a pocket of skin in the area where the nose or ear is missing.
In the past, bone has been replaced using actual segments of sterilized bone or bone powder or porous surgical steel seeded with bone cells which were then implanted. In most cases, repair to injuries was made surgically. Patients suffering from degeneration of cartilage had only pain killers and anti-inflammatories for relief.
Until recently, the growth of new cartilage from either transplantation or autologous or allogeneic cartilage has been largely unsuccessful. Consider the example of a lesion extending through the cartilage into the bone within the hip joint. Picture the lesion in the shape of a triangle with its base running parallel to the articular cavity, extending entirely through the hyaline cartilage of the head of the femur, and ending at the apex of the lesion, a full inch (2.54 cm) into the head of the femur bone. Presently, there is a need to successfully insert an implant device consisting of a macrostructure and a microstructure for containing and transporting cartilage cells and bone cells together with supporting nutrients, growth factors and morphogens, which will assure survival and proper future differentiation of these cells after transplantation into the recipient tissue defect. Presently, cartilage cells, called chondrocytes, when implanted along with bone cells, can degenerate into more bone cells because hyaline cartilage is an avascular tissue and must be protected from intimate contact with sources of high oxygen tension such as blood. Bone cells, in contrast, require high oxygen levels and blood.
Most recently, two different approaches to treating articular lesions have been advanced. One approach such as disclosed in U.S. Pat. No. 5,041,138 is coating bioderesorbable polymer fibers of a structure with chemotactic ground substances. No detached microstructure is used. The other approach such as disclosed in U.S. Pat. No. 5,133,755 uses chemotactic ground substances as a microstructure located in voids of a macrostructure and carried by and separate from the biodegradable polymer forming the macrostructure. Thus, the final spatial relationship of these chemotactic ground substances with respect to the bioresorbable polymeric structure is very different in U.S. Pat. No. 5,041,138 from that taught in U.S. Pat. No. 5,133,755.
The fundamental distinction between these two approaches presents three different design and engineering consequences. First, the relationship of the chemotactic ground substance with the bioresorbable polymeric structure differs between the two approaches. Second, the location of biologic modifiers carried by the device with respect to the device's constituent materials differs. Third, the initial location of the parenchymal cells differs.
Both approaches employ a bioresorbable polymeric structure and use chemotactic ground substances. However, three differences between the two approaches are as follows.
I. Relationship of Chemotactic Ground Substances with the Bioresorbable Polymeric Structure. PA1 II. Location of Biologic Modifiers Carried by a Device with Respect to the Device's Constituent Materials. PA1 III. Initial Location of the Parenchymal Cell. PA1 1) a severely limited quantity of chemotactic ground substance that can be incorporated within the device; and PA1 2) a surface area available for cell attachment that is limited by the surface area supplied by the structure polymer. PA1 1. The arrangement of fenestrated polymer strands of the tangential region produces a network of intercommunicating void spaces which have a horizontal orientation with respect to void spaces of the radial zone, thus making this construction anatomically specific for articular cartilage tissue. PA1 2. The cartilage region's radial zone provides void spaces in horizontal planes which penetrate the vertically orientated polymer sheets and create intercommunications between the vertically positioned void spaces. PA1 3. The radial zone of the cartilage region at the interface surface with the subchondral bone region provides a honeycomb pattern of pores with an uninterrupted space communicating from the interface surface, through the radial and tangential zones, to the pores which ultimately accesses the synovial fluid. PA1 4. The hydrophobic barrier creates a strategic zone without interrupting the continuity of the macrostructure polymer of the subchondral bone region and further without introducing any chemical change in the macrostructure polymer. PA1 5. The microstructure is strategically located within one, or multiple, discrete locales of the macrostructure void network while other locales of the macrostructure void network remain devoid of microstructure material. PA1 6. The concentration gradients of microstructure material are selectively varied within certain regions of macrostructure voids to affect different biologic characteristics critical to different tissue requirements. PA1 7. A microstructure is provided to a single anatomically specific device having a composition of multiple different materials in different regions of macrostructure voids according to the varying tissue and biologic characteristic requirements. PA1 8. The use of a microstructure within a macrostructure provides multiple locations for transport of one or more types of biologic modifier cargo: PA1 9. The three-dimensional configuration of the cell is preserved. PA1 10. The entire surface area of each cell is preserved in optimum condition for interaction with the microstructure and its cargo of biologically active agents. PA1 11. Each cell is coated with microstructure material which, in the case of hyaluronic acid, is composed of a high percentage of naturally occurring extracellular matrix. PA1 12. Free cells are maintained in a semi-fluid environment so that the cells can move to establish multiple regions of optimum cell density. PA1 13. The cells are maintained in close proximity to high concentrations of free, solubilized and unattached biologically active agents. PA1 14. A transport for biologically active agents is provided. PA1 15. A transport for osteoinductive/osteogenic and/or chondroinductive/chondrogenic agents, as well as other therapeutic substances (i.e. living cells appropriate for the tissue under treatment, cell nutrient media, varieties of growth factors, morphogens and other biologically active proteins) are provided. PA1 16. An electronegative environment is created which is conducive to osteogenesis/chondrogenesis. PA1 17. The need for more surgery to remove the device is eliminated since it is bioresorbable in its entirety. PA1 18. A transport for precursor repair cells to lesion repair sites is created. PA1 19. The attachment of free, precursor cells to the device and to the repair site is facilitated. PA1 1. Joins bioresorbable polymers of different architectures and chemical profiles into a single unit whose composite architectures are specifically ordered to duplicate the arrangements of parenchymal cells and stromal tissue of the tissue or organ under treatment and whose constituent polymers are specifically synthesized to possess chemical profiles appropriate for their particular locations within the whole. This object of the invention is expressed in the example of a device for treatment of articular cartilage defects in the most preferred form. The cartilage region architecture is joined to the subchondral bone region (cancellous bone) architecture to form a bioresorbable polymer implant having an anatomically specific architecture for articular cartilage. PA1 2. Strategically positions microstructure material in that specific portion of the complete device to perform the particular unique functions required by the particular tissues being treated. PA1 3. Segregates microstructure material within the anatomically specific device according to the special biologic functions of a particular implant. PA1 4. Delivers chondrocytes only to the cartilage region of the device and supports their life functions in the cartilage defect by sequestering the chondrocyte cell population together with the in vitro cell culture medium in its microstructure (alginate) gel. PA1 5. Presents enough chondrocytes to the subchondral bone region immediately adjacent to the cartilage region so as to assure that a competent osteo-chondral bond is established between the newly developed cartilage and the newly developed bone. PA1 6. Provides a bioresorbable structure to carry and to support cell attachment enhancing material such as a chemotactic ground substance which is in the form of a filamentous velour having incomplete, interconnecting intersticies. PA1 7. Generates electronegative potentials by maintaining an alginate or HY-fluid phase and PLA structural phase interface, as well as by the electronegative chemical property of alginate or HY alone. PA1 8. Creates biophysical conditions and environment such that exogenous electric signals can be applied to the implant device to produce a synergistic effect with the endogenous currents generated by alginate or HY/PLA surface interactions and the intrinsic electronegativity of the microstructure. PA1 9. Provides a unique juxtaposition of polylactate, alginate/hyaluronic acid and chemical osteoinductive/ osteogenic and/or chondroinductive/chondrogenic agents. PA1 10. Juxtaposes cell attachment enhancing material such as a chemotactic ground substance with a biodegradable polymer of either solid, open cell meshwork form, or in either form or both forms. PA1 11. Provides a biodegradable structure to transport and to support precursor repair cells for repair sites. PA1 12. Creates conditions and environments for facilitating the attachment of free, precursor cells for carriage to the repair site.
The design and engineering consequence of coating the polymer fibers with a chemotactic ground substance is that both materials become fused together to form a single unit from structural and spatial points of view. The spaces between the fibers of the polymer structure remain devoid of any material until after the cell culture substances are added.
In contrast, the microstructure approach uses chemotactic ground substances as well as other materials, separate and distinct from the bioresorbable polymeric macrostructure. The microstructure resides within the void spaces of the macrostructure and only occasionally juxtaposes the macrostructure. Additionally, the microstructure approach uses polysaccharides and chemotactic ground substances spacially separate from the macrostructure polymer and forms an identifiable microstructure, separate and distinct from the macrostructure polymer.
The design and engineering advantage to having a separate and distinct microstructure capable of carrying other biological active agents can be appreciated in the medical treatment of articular cartilage. RGD attachment moiety of fibronectin is a desirable substance for attaching chondrocytes cells to the lesion. However, RGD attachment moiety of fibronectin is not, by itself, capable of forming a microstructure of velour in the microstructure approach. Instead, RGD is blended with a microstructure material prior to investment within macrostructure interstices and is ultimately carried by the microstructure velour.
Coating only the polymer structure with chemotactic ground substances necessarily means that the location of the chemotactic ground substance is only found on the bioresorbable polymeric structure fibers. The microstructure approach uses the microstructure to carry biologic modifiers such as growth factors, morphogens, drugs, etc. The coating approach can only carry biologic modifiers with the biodegradable polymeric structure.
Because the coating approach attaches the chemotactic ground substances to the surfaces of the structure polymer and has no microstructure resident in the void volume of the device, the coating approach precludes the possibility of establishing a network of extracellular matrix material, specifically a microstructure, within the spaces between the fibers of the polymer structure once the device is fully saturated with cell culture medium. The coating approach predetermines that any cells introduced via culture medium will be immediately attracted to the surface of the structure polymer and attach thereto by virtue of the chemotactic ground substances on the polymer's surfaces.
The consequence of confining chemotactic ground substances to only the surfaces of the polymeric structure places severe restrictions on the number of cells that can be accommodated by the coated device. These restrictions on cell capacity are enforced by two limiting factors:
In contrast to the coating approach, the microstructure approach, by locating chemotactic ground substances in the void spaces of the device, makes available the entire void volume of the device to accommodate their chemotactic ground substance microstructure.
In so far as it relates to a biologic cell trap for controlled growth and guided tissue regeneration, recent years have increased knowledge concerning biological mechanisms involved in the restoration of periodontal defects which has led to a method of treatment known as Guided Tissue Regeneration. This concept is based on the theory of space maintenance for the periodontal bone defect under treatment. Soft tissue is removed from the defect and a barrier is placed between the surrounding soft tissue and the periodontal defect (void) in alveolar bone. The barrier prevents soft tissue from returning to the defect (void) while allowing the slower growing bone sufficient time to fill the void and reestablish attachment with the tooth. These barriers can be broken down into two major groups: 1) Bioresorbable/Bioerodable; and 2) Non-Bioresorbable/Bioerodable. Those barriers which are not bioresorbable (polytetrafluorethylene, titanium, etc.) must be removed by a second surgery resulting in additional surgical trauma and risk of damage to newly regenerated bone by compromise of its collateral circulation. Those barriers which are bioresorbable have one of two drawbacks. They are either solid, in which case they prevent interstitial fluid exchange, or they are permeable and allow rapid penetration of soft tissue through the device. Thus, a unique design is needed in order to limit or prevent tissue penetration while still allowing for free exchange of interstitial fluid.
U.S. Pat. Nos. 4,181,983 and 4,186,444 define porous bioresorbable polymer devices. These devices, designed to treat tissue deficiencies, are comprised of a bioresorbable polymer fabricated in architecture resembling cancellous bone, allowing for rapid and complete penetration of soft and hard tissue through the devices. U.S. Pat. No. 3,902,497 meets the general description of U.S. Pat. Nos. 4,181,983 and 4,186,444 and will also allow complete soft tissue penetration in a short period of time.
U.S. Pat. No. 4,442,655 teaches a fibrin matrix formed in an aqueous solution which, once placed in mammalian tissue,. will collapse and afford no barrier function to soft tissue invasion.
U.S. Pat. Nos. 4,563,489; 4,596,574; and 4,609,551, although different from U.S. Pat. Nos. 4,181,483 and 4,186,444, are designed to accomplish the same goal; repair tissue deficiencies and create a continuous, uninterrupted mend. This is also the goal of U.S. Pat. No. 5,041,138, in which the device is composed of branching bioresorbable sutures.
None of the aforementioned devices, however, is designed to operate as a cell trap or barrier. Each encourages rapid ingrowth of tissue which will escape the device and invade the defect void.